The present invention relates to novel nitrosourea derivatives and, more specifically, to novel 2-desoxy-sugar-nitrosoureas and 4-desoxy-sugar-nitrosoureas, to processes for their preparation and to their therapeutic uses.
It is known that various nitrosoureas have powerful cytostatic and oncostatic activity detected within the framework of pharmacological experiments and clinical treatment : this is the case, in particular, of (1,3-bis-2-chloroethyl)-1-nitrosourea [BCNU] marketed under the trademark "BICNU" (cf. Dictionnaire VIDAL 1984), of 1-(2-chloro-ethyl)-3-cyclohexyl nitrosourea [CCNU] marketed under the trademark "BELUSTINE" (cf. Dictionnaire VIDAL 1984) and 1-(2-chloro-ethyl)-3-(4-methyl-cyclohexyl)-nitrosourea [Me CCNU] : cf. G. MATHE and Y. KENIS : Expansion Scientifique, 1975, 3rd Ed. TLa Chimiotherapie des cancers (leucemies, hematosarcomes et tumeurs solides)" and T. H. WASSERMAN, M. SLAVIK & S. K. CARTER, Cancer Treat. Rev., 1974, 1, p. 131, "Review of CCNU in clinical cancer therapy". G. P. WHEELER et al. (Cancer Res., 1974, 34, 194) attribute their oncostatic action to an alkylation and a carbomoylation of proteins. It has also been suggested that their lypophilic character is essential in so far as it conditions the passage through cell membranes in particular the blood-brain barrier. However, these compounds have the drawback of showing certain toxicity, particularly hematological, at the doses at which they are revealed to be active. Consequently, this toxicity limits their use at doses less than those which seem necessary for the removal of cancer cells and has incited a team of researchers to aim at obtaining medicaments more active and less toxic than the preceding ones, by synthesizing derivatives of nitro soureas whose hydrophilic character is increased with respect to the preceding ones, such as sugar-nitrosoureas, in which the sugar molecule is ribose, xylose or glucose : cf. J. L. IMBACH et al, Biomedicine, 1975, 23, pp. 410-413, "The oncostatic and immunosuppressive action of new nitrosourea derivatives containing sugar radicals". Thus these authors have established the oncostatic action of the following four compounds on L 1210 leucemia and their low toxicity:1-(2-chloro-ethyl)3-(ribofuranosyl-2', 3'-isopropylidene-5-paranitro benzoate)-nitrosourea [RFCNU], 3-(2-chloro-1-ethyl-2'-desoxy-glucopyranosyl-14, 3',4",6'-tetracetate)-nitrosourea [GCNU], 1-(2-chloro-ethyl) 3-(ribopyranosyl-2',3',4'-triacetate)-nitrosourea [RPCNU] and 1-(2-chloro ethyl) 3-(xylopyranosyl 2',3',4'-triacetate)-nitrosourea [XPCNU]. These compounds are prepared by reacting the appropriate amino-sugar with 2-chloro-ethyl isocyanate, then by proceeding with nitrosation of the urea obtained.
These compounds are in oily form, a difficult physical state to handle in therapeutics. This is why, within the scope of the experiments been had to their solidification by blocking the hydroxy groups.
In a subsequent work J. L. MONTERO et al (Eur. J. Med. Chem. Chimica Therapeutica, mars/avril 1976, 11, n 2, pp. 183-187 : "Synthese de nouvelles glycosylnitrosourees a visees oncostatiques - les 1-nitrosoureido-1-desoxy-glucopyranoses"), described glycosyl-nitrosoureas in which the sugar-nitrogen bond is located in an anomeric position, which has oncostatic activity, namely 1-[3-(2-position, which has oncostatic activity, namely 1-[3-(2-chloro-ethyl) 3-nitroso-ureido]-1-beta-D-glucopyranose and 2,3,4,6-tetra-O-acetyl 1-[3-(2-chlor-ethyl) nitroso-3-ureido]-1-desoxy-beta-D-glucopyranose, and which represents in addition the advantage of lower toxicity on the bone marrow and not being diabetogenic, whereas streptozotocine or 2-desoxy-2-(3-methyl-2-nitrosoureido)-D-glucopyranose, which is a compound of natural origin, presents antibiotic, antineoplasic properties, and also presents undesirable diabetogenic properties as well as a high renal and hematological toxicity (ci. Drugs of the future, vol. lV, n 2, 1979, pp. 137-139).
One of the aspects of the invention is to provide novel nitrosourea derivatives, for which the profile of the activity curve shows its maximum at a dosage far below the threshold of the toxicity.
Another aspect of the invention is to provide novel nitrosourea derivatives having a good therapeutic index.
It is another aspect of the invention to provide also novel nitrosourea derivatives having physical properties enabling their use in therapeutics.
Another aspect of the invention is to provide novel nitrosourea derivatives having a solid and stable form.